Pyrimidine matrix metalloproteinase inhibitors

ABSTRACT

Selective MMP-13 inhibitors are pyrimidine derivatives of the formula  
                 
 
     or a pharmaceutically acceptable salt thereof,  
     wherein:  
     R 2  is hydrogen, halo, hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, NO 2 , NR 4 R 5 , CN, or CF 3 ;  
     E is independently O or S;  
     A and B independently are OR 4  or NR 4 R 5 ; R 4  and R 5  independently are H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (CH 2 ) n  aryl, (CH 2 ) n  cycloalkyl, (CH 2 )n heteroaryl, or R 4  and R 5  when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S, or NH, and optionally substituted or unsubstituted;  
     n is an integer of from 0 to 6.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of priority to U.S. provisionalapplication No. 60/268,779, filed Feb. 14, 2001.

FIELD OF THE INVENTION

[0002] This invention relates to pyrimidine derivatives which inhibitmatrix metalloproteinase enzymes and thus are useful for treatingdiseases resulting from tissue breakdown such as heart disease, multiplesclerosis, osteo- and rheumatoid arthritis, atherosclerosis, andosteoporosis.

BACKGROUND OF THE INVENTION

[0003] Matrix metalloproteinases (sometimes referred to as MMPs) arenaturally occurring enzymes found in most mammals. Over-expression andactivation of MMPs, or an imbalance between MMPs and inhibitors of MMPs,have been suggested as factors in the pathogenesis of diseasescharacterized by the breakdown of extracellular matrix or connectivetissues.

[0004] Stromelysin-1 and gelatinase A are members of the MMP family.Other members include fibroblast collagenase (MMP-1), neutrophilcollagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9),stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7),collagenase 3 (MMP-13), TNF-alpha converting enzyme (TACE), and othernewly discovered membrane-associated matrix metalloproteinases (Sato H.,Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M.,Nature, 1994;370:61-65). These enzymes have been implicated with anumber of diseases which result from breakdown of connective tissue,including such diseases as rheumatoid arthritis, osteoarthritis,osteoporosis, periodontitis, multiple sclerosis, gingivitis, cornealepidermal and gastric ulceration, atherosclerosis, neointimalproliferation which leads to restenosis and ischemic heart failure, andtumor metastasis. A method for preventing and treating these and otherdiseases is now recognized to be by inhibiting matrix metalloproteinaseenzymes, thereby curtailing and/or eliminating the breakdown ofconnective tissues that results in the disease states.

[0005] There is a catalytic zinc domain in matrix metalloproteinasesthat is typically the focal point for inhibitor design. The modificationof substrates by introducing zinc-chelating groups has generated potentinhibitors such as peptide hydroxamates and thiol-containing peptides.Peptide hydroxamates and the natural endogenous inhibitors of MMPs(TIMPs) have been used successfully to treat animal models of cancer andinflammation. MMP inhibitors have also been used to prevent and treatcongestive heart failure and other cardiovascular diseases, U.S. Pat.No. 5,948,780.

[0006] A major limitation on the use of currently known MMP inhibitorsis their lack of specificity for any particular enzyme. Recent data hasestablished that specific MMP enzymes are associated with some diseases,with no effect on others. The MMPs are generally categorized based ontheir substrate specificity, and indeed the collagenase subfamily ofMMP-1, MMP-8, and MMP-13 selectively cleave native interstitialcollagens, and thus are associated only with diseases linked to suchinterstitial collagen tissue. This is evidenced by the recent discoverythat MMP-13 alone is over expressed in breast carcinoma, while MMP-1alone is over expressed in papillary carcinoma (see Chen et al., J. Am.Chem. Soc., 2000;122:9648-9654).

[0007] There appears to be few selective inhibitors of MMP-13 reported.A compound named WAY-170523 has been reported by Chen et al., supra.,2000, and a few other compounds are reported in PCT InternationalApplication Publication Number WO 01/63244 A1, as allegedly selectiveinhibitors of MMP-13. Further, United States Patent Number 6,008,243discloses inhibitors of MMP-13. However, no selective or nonselectiveinhibitor of MMP-13 has been approved and marketed for the treatment ofany disease in any mammal. Accordingly, the need continues to find newlow molecular weight compounds that are potent and selective MMPinhibitors, and that have an acceptable therapeutic index oftoxicity/potency to make them amenable for use clinically in theprevention and treatment of the associated disease states. An object ofthis invention is to provide a group of selective MMP-13 inhibitorcompounds characterized as being pyrimidine derivatives.

SUMMARY OF THE INVENTION

[0008] This invention provides a method for inhibiting matrixmetalloproteinase enzymes, and especially MMP-13, using a pyrimidine oranalog thereof. The invention is more particularly directed to a methodfor inhibiting MMP enzymes comprising administering to a host an MMPinhibiting amount of a compound defined by Formula I

[0009] or a pharmaceutically acceptable salt thereof,

[0010] wherein:

[0011] R² is hydrogen, halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, C₂-C₆ alkynyl, NO₂, NR⁴R⁵, CN, or CF₃;

[0012] E is independently O or S;

[0013] A and B independently are OR⁴ or NR⁵R⁶; R⁴ and R⁵ independentlyare H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (CH₂)_(n) aryl,(CH₂)_(n) cycloalkyl, (CH₂)_(n) heteroaryl, or R⁴ and R⁵ when takentogether with the nitrogen to which they are attached complete a 3- to8-membered ring, containing carbon atoms and optionally containing aheteroatom selected from O, S, or NH, and optionally substituted orunsubstituted; and

[0014] n is an integer from 0 to 6.

[0015] Another embodiment o f the invention is a method of inhibitingenzymes in a host comprising administering a compound of Formula II

[0016] or a pharmaceutically acceptable salt thereof, wherein R² is asdefined above, and each R⁴ independently is as defined above.

[0017] Another embodiment of the invention is a method for inhibitingMMP enzymes comprising administering a compound of Formula III

[0018] or a pharmaceutically acceptable salt thereof, wherein R² is asdefined above, and each R⁴ and R⁵ independently are as defined above.

[0019] Another embodiment of the invention is a method for inhibitingMMP enzymes comprising administering MMP inhibitors having Formula IV

[0020] or a pharmaceutically acceptable salt thereof, wherein n and R²are as defined above, and R⁶, R⁷, R⁸, and R⁹ independently are hydrogen,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, nitro, or NH₂.

[0021] Another embodiment of the invention is a method for inhibitingMMP enzymes comprising administering an MMP inhibitor of Formula V

[0022] or a pharmaceutically acceptable salt thereof, wherein n and R²are as defined above, and each Ar independently is aryl or Het, whereinaryl is phenyl or substituted phenyl, and Het is an unsubstituted orsubstituted heteroaryl group.

[0023] Compounds of Formulas I, II, III, IV, and V are provided asfurther embodiments of this invention.

[0024] Another embodiment of the invention are amides of Formula Iwherein one or both of A and B is NR⁴R⁵, wherein R⁴ and R⁵ are asdefined above.

[0025] Another embodiment of the invention are compounds selected from:

[0026] Pyrimidine-4,6-dicarboxylic acid, (4-chloro-benzylamide),[(1,3-benzodioxol-5-ylmethyl)-amide];

[0027] Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),[(1,3-benzodioxol-5-ylmethyl)-amide];

[0028] Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(4-methoxy-benzylamide);

[0029] Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(3-methoxy-benzylamide);

[0030] Pyrimidine-4,6-dicarboxylic acid, (4-carbomethoxy-benzylamide),(3-methoxy-benzylamide);

[0031] Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(3-pyridylmethylamide);

[0032] Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(3-thiophenemethylamide);

[0033] Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzothiadiazol-5-ylmethyl) amide,[(1,3-benzodioxol-5-ylmethyl)-amide];

[0034] Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzooxadiazol-5-ylmethyl) amide,[(1,3-benzodioxol-5-ylmethyl)-amide];

[0035] Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzothiadiazol-5-ylmethyl) amide, (4-methoxy-benzylamide);

[0036] Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzothiadiazol-5-ylmethyl) amide, (3-methoxy-benzylamide);

[0037] Pyrimidine-4,6-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl)ester;

[0038] Pyrimidine-4,6-dicarboxylic acid, bis-(4-chloro-benzylamide);

[0039] Pyrimidine-4,6-dicarboxylic acid,bis-[(1,3-benzodioxol-5-ylmethyl)-amide];

[0040] Pyrimidine-4,6-dicarboxylic acid, bis-(4-methoxy-benzylamide);

[0041] Pyrimidine-4,6-dicarboxylic acid, bis-(3-methoxy-benzylamide);

[0042] Pyrimidine-4,6-dicarboxylic acid, bis-(4-carboxy-benzylamide);and

[0043] Pyrimidine-4,6-dicarboxylic acid,bis-(4-carbomethoxy-benzylamide).

[0044] Another embodiment of this invention is a pharmaceuticallyacceptable salt of the above-named compounds.

[0045] Another embodiment of this invention is a pharmaceuticalcomposition, comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, admixed with a pharmaceutically acceptablecarrier, excipient, or diluent.

[0046] Another embodiment of this invention is a pharmaceuticalcomposition comprising a compound of Formulas II, III, IV, or V, or apharmaceutically acceptable salt thereof, admixed with apharmaceutically acceptable carrier, excipient, or diluent.

[0047] Another embodiment of this invention is a pharmaceuticalcomposition comprising a compound selected from:

[0048] Pyrimidine-4,6-dicarboxylic acid, (4-chloro-benzylamide),[(1,3-benzodioxol-5-ylmethyl)-amide];

[0049] Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),[(1,3-benzodioxol-5-ylmethyl)-amide];

[0050] Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(4-methoxy-benzylamide);

[0051] Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(3-methoxy-benzylamide);

[0052] Pyrimidine-4,6-dicarboxylic acid, (4-carbomethoxy-benzylamide),(3-methoxy-benzylamide);

[0053] Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(3-pyridylmethylamide);

[0054] Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(3-thiophenemethylamide);

[0055] Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzothiadiazol-5-ylmethyl) amide,[(1,3-benzodioxol-5-ylmethyl)-amide];

[0056] Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzooxadiazol-5-ylmethyl) amide,[(1,3-benzodioxol-5-ylmethyl)-amide];

[0057] Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzothiadiazol-5-ylmethyl) amide, (4-methoxy-benzylamide);

[0058] Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzothiadiazol-5-ylmethyl) amide, (3-methoxy-benzylamide);

[0059] Pyrimidine-4,6-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl)ester;

[0060] Pyrimidine-4,6-dicarboxylic acid, bis-(4-chloro-benzylamide);

[0061] Pyrimidine-4,6-dicarboxylic acid,bis-[(1,3-benzodioxol-5-ylmethyl)-amide];

[0062] Pyrimidine-4,6-dicarboxylic acid, bis-(4-methoxy-benzylamide);

[0063] Pyrimidine-4,6-dicarboxylic acid, bis-(3-methoxy-benzylamide);

[0064] Pyrimidine-4,6-dicarboxylic acid, bis-(4-carboxy-benzylamide);and

[0065] Pyrimidine-4,6-dicarboxylic acid,bis-(4-carbomethoxy-benzylamide), or a pharmaceutically acceptable saltthereof, admixed with a pharmaceutically acceptable carrier, excipient,or diluent.

[0066] Another embodiment of this invention is a pharmaceuticalcomposition comprising a pharmaceutically acceptable salt of theabove-named compounds, admixed with a pharmaceutically acceptablecarrier, excipient, or diluent.

[0067] A further embodiment of this invention is a method for treating adisease mediated by an MMP-13 enzyme, comprising administering to apatient suffering from such a disease an effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt thereof.

[0068] Another embodiment of this invention is a method for treating adisease mediated by an MMP-13 enzyme, comprising administering to apatient suffering from such a disease an effective amount of a compoundof Formula II, III, IV, or V, or an above-named compound, or any otherabove-described compound embodiment, including a compound of Formula Iwherein one or both of A and B is NR⁴R⁵, wherein R⁴ and R⁵ are asdefined above, or a pharmaceutically acceptable salt thereof.

[0069] Another embodiment of this invention is a method of treatmentaccording to this invention is treatment of a disease selected fromcancer, (especially breast carcinoma), inflammation, osteoarthritis,rheumatoid arthritis, and heart failure, comprising administering to apatient in need thereof a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

[0070] Another embodiment of this invention is a method of treatmentaccording to this invention is treatment of a disease selected fromcancer, (especially breast carcinoma), inflammation, osteoarthritis,rheumatoid arthritis, and heart failure, comprising administering to apatient suffering from such a disease an effective amount of a compoundof Formula II, II, IV, or V, or an above-named compound, or any otherabove-described compound embodiment, including a compound of Formula Iwherein one or both of A and B is NR⁴R⁵, wherein R⁴ and R⁵ are asdefined above, or a pharmaceutically acceptable salt thereof.

[0071] A further embodiment is use of a compound of Formula I, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a disease mediated by an MMP-13 enzyme.Preferred is use of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, wherein one or both of A and B is NR⁴R⁵,wherein R⁴ and R⁵ are as defined above. Also preferred is use of acompound of Formula II, III, IV, or V, or a pharmaceutically acceptablesalt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0072] The compounds to be used in the method of inhibiting MMP enzymesprovided by this invention are those defined by Formula I. In Formula I,R¹ to R⁹ include “C₁-C₆ alkyl” groups. These are straight and branchedcarbon chains having from 1 to 6 carbon atoms. Examples of such alkylgroups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, andn-hexyl. The alkyl groups can be substituted if desired, for instancewith groups such as hydroxy, amino, alkyl, and dialkylamino, halo,trifluoromethyl, carboxy, nitro, and cyano.

[0073] “Alkenyl” means straight and branched hydrocarbon radicals havingfrom 2 to 6 carbon atoms and one double bond and includes ethenyl,3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like.

[0074] “Alkynyl” means straight and branched hydrocarbon radicals havingfrom 2 to 6 carbon atoms and one triple bond and includes ethynyl,3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.

[0075] “Cycloalkyl” means a monocyclic or polycyclic hydrocarbyl groupsuch as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl,adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, andcyclopentyl. Such groups can be substituted with groups such as hydroxy,keto, and the like. Also included are rings in which 1 to 3 heteroatomsreplace carbons. Such groups are termed “heterocyclyl,” which means acycloalkyl group also bearing at least one heteroatom selected from O,S, or NR², examples being oxiranyl, pyrrolidinyl, piperidyl,tetrahydropyranyl, and morpholinyl.

[0076] “Alkoxy” refers to the alkyl groups mentioned above bound throughoxygen, examples of which include methoxy, ethoxy, isopropoxy,tert-butoxy, and the like. In addition, alkoxy refers to polyethers suchas —O—(CH₂)₂—O—OH₃, and the like.

[0077] “Acyl” means an R group that is an alkyl or aryl (Ar) groupbonded through a carbonyl group, i.e., R—C(O)—, where R is alkyl oraryl. For example, acyl includes a C₁-C₆ alkanoyl, including substitutedalkanoyl, wherein the alkyl portion can be substituted by NR⁴R⁵ or acarboxylic or heterocyclic group. Typical acyl groups include acetyl,benzoyl, isonicotinoyl, and the like.

[0078] The alkyl, alkenyl, alkoxy, and alkynyl groups described aboveare optionally substituted, preferably by 1 to 3 groups selected fromNR⁴R⁵, phenyl, substituted phenyl, thio C₁-C₆ alkyl, C₁-C₆ alkoxy,hydroxy, carboxy, C₁-C₆ alkoxycarbonyl, acyl, halo, nitrile, cycloalkyl,and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, andsulfur. “Substituted nitrogen” means nitrogen bearing C₁-C₆ alkyl or(CH₂)_(n) Ph where n is 1, 2, or 3. Perhalo and polyhalo substitution isalso embraced.

[0079] Examples of substituted alkyl groups include 2-aminoethyl,acetylmethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl,2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl,methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl,4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl,3-morpholinopropyl, piperazinylmethyl, 4-benzoylbutyl, and2-(4-methylpiperazinyl)ethyl.

[0080] Examples of substituted alkynyl groups include 2-methoxyethynyl,2-benzoylethylyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl),3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl,4-cyclobutyl-4-hexenyl, and the like.

[0081] Typical substituted alkoxy groups include aminomethoxy,acetoxymethoxy, trifluoromethoxy, 2-diethylaminoethoxy,2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and thelike.

[0082] Further, examples of substituted alkyl, alkenyl, and alkynylgroups include dimethylaminomethyl, carboxymethyl,4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl,4-morpholinobutyl, 4-tetrahydropyrinidylbutyl,3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl,3-chlorophenylmethyl, and the like.

[0083] The terms “Ar” and “aryl” refer to unsubstituted and substitutedaromatic groups. Heteroaryl (Het) groups have from 4 to 9 ring atoms,from 1 to 4 ring atoms of which are independently selected from thegroup consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2heteroatoms in a 5- or 6-membered aromatic ring. Mono- and bicyclicaromatic ring systems are included in the definition of aryl andheteroaryl. Preferred substituent groups include alkyl, alkoxy, halo,amino, alkylamino, dialkylamino, CN, CF₃, thioalkyl, acyl and hydroxy.Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl,2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl,2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl,naphthyl, 4,7-dichloronaphthyl, morpholinyl, indolyl, benzotriazolyl,indazolyl, pyrrole, pyrazole, imidazole, thiazole, methylenedioxyphenyl,benzo-2,1,3-thiadiazole, benzo-2,1,3-oxadiazole, and the like.

[0084] Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or3 groups independently selected from the group consisting of alkyl,alkoxy, thio, thioalkyl, halo, hydroxy, —COOR⁷, trifluoromethyl, nitro,amino of the formula -NR⁴R⁵, and T(CH₂)_(m)QR⁴ or T(CH₂)_(m)CO₂R⁴wherein m is 1 to 6, T is O, S, NR⁴, N(O)R⁴, NR⁴R⁶Y, or CR⁴R⁵, Q is O,S, NR⁵, N(O)R⁵, or NR⁵R⁶Y wherein R⁴ and R⁵ are as described above, andR⁷ is hydrogen, alkyl, or substituted alkyl, for example, methyl,trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxygroups can be substituted as defined above. For example, typical groupsare carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, andalkoxyalkyl. Typical substituted aryl groups include 2,6-dichlorophenyl,3-hydroxyphenyl, 1 ,3-benzodioxolyl, 4-dimethylaminophenyl,2,4,6-triethoxyphenyl, 3-cyanophenyl, 4-methylthiophenyl, and3,5-dinitrophenyl.

[0085] Examples of NR⁴R⁵ groups include amino, methylamino,di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino,3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino,4-diethylaminobutyl amino, and 3-carboxypropionyl amino. R⁴ and R⁵ canbe taken together with the nitrogen to which they are attached to form aring having 3 to 7 carbon atoms and 1, 2, or 3 heteroatoms selected fromthe group consisting of nitrogen, substituted nitrogen, oxygen, andsulfur. Examples of such cyclic NR⁴R⁵ groups include pyrrolidinyl,piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl,piperidinyl, pyrazinyl, morpholinyl, and the like.

[0086] “Halo” includes fluoro, chloro, bromo, and iodo.

[0087] The term “patient” means a mammal. Preferred patients includehumans, cats, dogs, cows, horses, pigs, and sheep.

[0088] The term “animal” means a mammal. Preferred animals are includehumans, rats, mice, guinea pigs, rabbits, monkeys, cats, dogs, cows,horses, pigs, and sheep.

[0089] The phrases “therapeutically effective amount” and “effectiveamount” are synonymous unless otherwise indicated, and mean an amount ofa compound of the present invention that is sufficient to improve thecondition, disease, or disorder being treated. Determination of atherapeutically effective amount, as well as other factors related toeffective administration of a compound of the present invention to apatient in need of treatment, including dosage forms, routes ofadministration, and frequency of dosing, may depend upon the particularsof the condition that is encountered, including the patient andcondition being treated, the severity of the condition in a particularpatient, the particular compound being employed, the particular route ofadministration being employed, the frequency of dosing, and theparticular formulation being employed. Determination of atherapeutically effective treatment regimen for a patient is within thelevel of ordinary skill in the medical or veterinarian arts. In clinicaluse, an effective amount may be the amount that is recommended by theU.S. Food and Drug Administration, or an equivalent foreign agency.

[0090] The phrase “admixed” or “in admixture” means the ingredients somixed comprise either a heterogeneous or homogeneous mixture. Preferredis a homogeneous mixture.

[0091] The phrases “pharmaceutical preparation” and “preparation” aresynonymous unless otherwise indicated, and include the formulation ofthe active compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Pharmaceuticalpreparations are fully described below.

[0092] The phrase “anticancer effective amount” means an amount ofinvention compound, or a pharmaceutically acceptable salt thereof,sufficient to inhibit, halt, or cause regression of the cancer beingtreated in a particular patient or patient population. For example inhumans or other mammals, an anticancer effective amount can bedetermined experimentally in a laboratory or clinical setting, or may bethe amount required by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular cancerand patient being treated.

[0093] The phrase “MMP-13 inhibiting amount” means an amount ofinvention compound, or a pharmaceutically acceptable salt thereof,sufficient to inhibit an enzyme matrix metalloproteinase-13, including atruncated form thereof, including a catalytic domain thereof, in aparticular animal or animal population. For example in a human or othermammal, an MMP-13 inhibiting amount can be determined experimentally ina laboratory or clinical setting, or may be the amount required by theguidelines of the United States Food and Drug Administration, orequivalent foreign agency, for the particular MMP-13 enzyme and patientbeing treated.

[0094] It should be appreciated that the matrix metalloproteinasesinclude the following enzymes:

[0095] MMP-1, also known as interstitial collagenase, collagenase-1, orfibroblast-type collagenase;

[0096] MMP-2, also known as gelatinase A or 72 kDa Type IV collagenase;

[0097] MMP-3, also known as stromelysin or stromelysin-1;

[0098] MMP-7, also known as matrilysin or PUMP-1;

[0099] MMP-8, also known as collagenase-2, neutrophil collagenase, orpolymorphonuclear-type (“PMN-type”) collagenase;

[0100] MMP-9, also known as gelatinase B or 92 kDa Type IV collagenase;

[0101] M-10, also known as stromelysin-2;

[0102] MMP-11, also known as stromelysin-3;

[0103] MMP-12, also known as metalloelastase;

[0104] MMP-13, also known as collagenase-3;

[0105] MMP-14, also known as membrane-type (“MT”) 1-MMP or MT1-MMP;

[0106] MMP-15, also known as MT2-MMP;

[0107] MMP-16, also known as MT3-MMP;

[0108] MMP-17, also known as MT4-MMP;

[0109] MMP-18; and

[0110] MMP-19.

[0111] Other MMPs are known, including MMP-26, which is also known asmatrilysin-2.

[0112] One aspect of the present invention is compounds of Formula I, ora pharmaceutically acceptable salt thereof, that are selectiveinhibitors of the enzyme MMP-13. A selective inhibitor of MMP-13, asused in the present invention, is a compound that is ≧5 times morepotent in vitro versus MMP-13 than versus at least one other matrixmetalloproteinase enzyme such as, for example, MMP-1, MMP-2, MMP-3,MMP-7, MMP-8, MMP-9, or MMP-14, or versus tumor necrosis factor alphaconvertase (“TACE”). A preferred aspect of the present invention iscompounds that are selective inhibitors of MMP-13 versus MMP-1.

[0113] Still other aspects of the present invention are compounds ofFormula I, or a pharmaceutically acceptable salt thereof, that areselective inhibitors of MMP-13 versus 2, 3, 4, 5, 6, or 7 other MMPenzymes, or versus TACE and 1, 2, 3, 4, 5, 6, or 7 other MMP enzymes.Other aspects of the present invention are compounds of Formula I, or apharmaceutically acceptable salt thereof, that are >10 times, ≧20 times,≧50 times, ≧100 times, or ≧1000 times more potent versus MMP-13 thanversus at least one of any other MMP enzyme or TACE.

[0114] It should be appreciated that determination of proper dosageforms, dosage amounts, and routes of administration, is within the levelof ordinary skill in the pharmaceutical and medical arts, and isdescribed below.

[0115] The term “IC₅₀” means the concentration of test compound requiredto inhibit activity of a biological target, such as a receptor orenzyme, by 50%.

[0116] The phrase “catalytic domain” means the domain containing acatalytic zinc cation of the MMP enzyme, wherein the MMP enzyme contains2 or more domains. A catalytic domain includes truncated forms thereofthat retain at least some of the catalytic activity of MMP-13 orMMP-13CD. For example, the collagenases, of which MMP-13 is a member,have been reported to contain a signal peptide domain, a propeptidedomain, a catalytic domain, and a hemopexin-like domain (Ye Qi-Zhuang,Hupe D., Johnson L., Current Medicinal Chemistry, 1996;3:407418).

[0117] The phrase “a method for inhibiting MMP-13” includes methods ofinhibiting full length MMP-13, truncated forms thereof that retaincatalytic activity, including forms that contain the catalytic domain ofMMP-13, as well as the catalytic domain of MMP-13 alone, and truncatedforms of the catalytic domain of MMP-13 that retain at least somecatalytic activity.

[0118] It should be appreciated that it has been shown previously (YeQi-Zhuang, et al., 1996, supra) that inhibitor activity against acatalytic domain of an MMP is predictive of the inhibitor activityagainst the respective full-length enzyme.

[0119] The compounds to be used in the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

[0120] The compounds of Formula I may have chiral centers, and thus canexist as racemic mixtures and individual enantiomers. All such isomericforms can be used in the method of this invention and are provided asnew compounds.

[0121] The compounds of Formula I are capable of further forming bothpharmaceutically acceptable formulations comprising salts, including butnot limited to acid addition and/or base salts, solvents and N-oxides ofa compound of Formula I. This invention also provides pharmaceuticalformulations comprising a compound of Formula I together with apharmaceutically acceptable carrier, diluent, or excipient. All of theseforms can be used in the method of the present invention.

[0122] Pharmaceutically acceptable acid addition salts of the compoundsof Formula I include salts derived form inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic,phosphorus, and the like, as well as the salts derived from organicacids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated arethe salts of amino acids such as arginate, gluconate, galacturonate, andthe like; see, for example, Berge et al., “Pharmaceutical Salts,” J. ofPharmaceutical Science, 1977;66:1-19.

[0123] The acid addition salts of the basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

[0124] Pharmaceutically acceptable base addition salts are formed withmetals or amines, such as alkali and alkaline earth metal hydroxides, orof organic amines. Examples of metals used as cations are sodium,potassium, magnesium, calcium, and the like. Examples of suitable aminesare N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see,for example, Berge et al., supra., 1977.

[0125] The base addition salts of acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. The free acid formmay be regenerated by contacting the salt form with an acid andisolating the free acid in a conventional manner. The free acid formsdiffer from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid for purposes of the presentinvention.

[0126] The compounds of the present invention can be formulated andadministered in a wide variety of oral and parenteral dosage forms,including transdermal and rectal administration. All that is required isthat an MMP inhibitor be administered to a mammal suffering from adisease in an effective amount, which is that amount required to causean improvement in the disease and/or the symptoms associated with suchdisease. It will be recognized to those skilled in the art that thefollowing dosage forms may comprise as the active component, either acompound of Formula I or a corresponding pharmaceutically acceptablesalt or solvate of a compound of Formula I.

[0127] The invention compounds are prepared by methods well known tothose skilled in the art of organic chemistry. The compounds of FormulaI are prepared utilizing commercially available starting materials, orreactants that are readily prepared by standard organic synthetictechniques. A typical synthesis of the invention compounds of Formula Iis shown in Scheme 1 below. The first step in Scheme 1 comprisesreacting a diacid with a chlorinating reagent such as thionyl chlorideor oxalyl chloride in a nonprotic solvent such as dichloromethane (DCM)to give the diacid chloride. This acid chloride can then be reacted withan amine, NHR⁴R⁵, in excess or with an organic base such astriethylamine, to give a bis-amide of Formula I. Alternately, the acidchloride can be reacted with an alcohol, R⁴OH, in a nonprotic solventsuch as dichloromethane along with an organic or inorganic base such astriethylamine or potassium carbonate to give a bis-ester of Formula I.The bis-ester can in some circumstances be reacted with an amine,NHR⁴R⁵, at elevated temperatures to give a bis-amide of Formula I. Thediacid can also be reacted with an alkyl halide in a nonprotic solventcontaining an organic or inorganic base to give a bis-ester of FormulaI. A third sequence involves the reaction of the diacid withhydroxybenzotriazole, HOBt, and dicyclohexylcarbodiimide, DCC, and anamine, NHR⁴R⁵, in a solvent such as dimethylformamide, DMF, ordichloromethane to give a bis-amide of Formula I.

[0128] Compounds of Formula I have also been synthesized usingcombinatorial techniques, Scheme 2. The diacid chloride is bound to aresin such as Marshall resin to give a bound acid chloride. The boundacid chloride is then reacted with an amine, NHR⁴R⁵, in the presence oftriethylamine in a solvent such as DCM to give a resin-bound amide. Theresin is then cleaved by reaction with an amine, NHR⁴R⁵, in dioxane inthe presence of an organic base to give a bis-amide of Formula I,wherein each R⁴ and R⁵ independently are as defined above.

[0129] The following detailed examples further illustrate the synthesisof typical invention compounds of Formula I. The examples arerepresentative only, and are not to be construed as limiting theinvention in any respect.

EXAMPLE 1 Pyrimidine-4,6-dicarboxylic Acid, Bis-benzylamide

[0130] Pyrimidine-4,6-dicarboxylic acid is dissolved in dichloromethane(DCM) at 24° C. To the solution is added three equivalents of thionylchloride. The reaction mixture is stirred at 24° C. for 1 hour. Thereaction mixture is concentrated by evaporation of the solvent underreduced pressure to give an oil. The oil is dissolved in ethyl acetate,and three equivalents of benzylamine are added. The reaction mixture isstirred at 24° C. for 3 hours. The solvent is than removed byevaporation under reduced pressure to give an oil. The oil is purifiedby chromatography over silica gel, eluting with hexane-ethyl acetate(9:1) to 100% ethyl acetate. The fractions shown by thin layerchromatography to contain a single product component are combined andconcentrated to dryness under reduced pressure to give the titlecompound.

EXAMPLE 2 Combinatorial Synthesis Method Loading of the Resin is CarriedOut as Follows

[0131] Marshall resin (15.2 g, 21.25 mmol) is swollen in DCM (300 mL) ina 500-mL resin tube (CAUTION: Slightly exothermic, the DCM may boil),and the mixture is allowed to cool. Once the mixture is cooled, the tubeis capped and agitated slowly for 5 minutes, venting frequently. The DCMis drained to waste. The DCM wash is repeated two additional times, thenthe resin is resuspended in DCM (300 mL), and triethylamine (TEA, 3.2 g,32 mmol, 1.5 mol. eq.) is added slowly. The resulting mixture is swirledfor 5 minutes, and pyrimidine-4,6-dicarboxylic acid dichloride (17.2 g,85 mmol, 4 eq) is added in one portion. The resin tube is capped,carefully secured in a wrist shaker, and inverted for 36 hours.

[0132] After 36 hours, a slight darkening of the resin may be noted. Thereaction solvent is drained, and the residual resin is washed threetimes with DCM (200 mL) and two times with diethyl ether (200 mL). Theresin is dried in vacuo for 24 hours. Resin loading is determined bothby weight gain and by total chloride determination. Typical loading isabout 1.1 mmol/g.

Resin Distribution is Performed as Follows

[0133] A Miniblock resin loader is calibrated for each resin used in theprotocol. The weight in milligrams of resin added per well is recorded,and the number of millimoles per well of boundpyrimidine-4,6-dicarboxylic acid chloride is calculated. Using thiscalibration and the loading for each resin, 0.15 mmol of resin isdistributed into each reaction tube. The valve on the block is closed.

Amine Solution Prep

[0134] An “A” amine set (NHR⁴R⁵) is diluted to 0.5 M in DCM. A 0.2 Msolution of TEA in DCM (1.5 mL per reaction) is prepared. A 0.2 Msolution of TEA in dioxane (1.5 mL per reaction) is prepared. A “B”amine set (NHR⁴R⁵) is diluted to 0.5 M in dioxane.

Addition of Amine A

[0135] The TEA solution in DCM from above (1.5 mL) is added to eachreaction tube, then using the Miniblock Map as a guide, the appropriate“A” amine (315 μL, 1.05 eq) is distributed. The mixtures are shaken for24 hours. After 24 hours, the reaction block is placed on a filtrationstation without a collection block, and the reactions are drained towaste. The valve is closed, and 2 mL of DCM is added. The mixtures areshaken for 2 minutes, and the reactions are drained to waste again.Unless the following step is to be carried out immediately, the reactionblocks are preferably stored under vacuum.

Addition of Amine B/resin Cleavage

[0136] The TEA solution in dioxane from above (1.5 mL) is added to eachreaction tube, then using the Miniblock Map as a guide, the appropriate“B” amine (300 μL, 1.05 eq) is distributed. The mixture is shaken for 72hours. After 72 hours, the reaction block is placed on a filtrationstation with a labeled collection block, and the reactions are drained.The valve is closed, 2 mL of DCM is added, and the mixture is shaken for2 minutes. The reactions are drained into the collection tubes.

Analysis

[0137] The products in the tubes may be identified by loop massspectrometry after first evaporating the DCM from the MS samples.

Concentrate

[0138] The samples are concentrated in a Genevac.

[0139] The invention compounds of Formula I can be evaluated in standardassays for their ability to inhibit the activity of various MMP enzymes.The assays that can be used to evaluate the biological activity of theinvention compounds are well known and routinely used by those skilledin the study of MMP inhibitors and their use to treat clinicalconditions. The assays measure the amount by which a test compoundreduces the hydrolysis of a thiopeptolide substrate catalyzed by amatrix metalloproteinase enzyme. Such assays are described in detail byYe et al., in Biochemistry, 1992;31(45):11231-11235, which isincorporated herein by reference.

[0140] Thiopeptolide substrates show virtually no decomposition orhydrolysis in the absence of a matrix metalloproteinase enzyme. Atypical thiopeptolide substrate commonly utilized for assays isAc-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt. A 100-μL assay mixture willcontain 50 mM of N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acidbuffer (“HEPES”) at pH 7.0, 10 mM CaC₁ ₂, 100 μM thiopeptolidesubstrate, and 1 mM 5,5′-dithio-bis-(2-nitro-benzoic acid) (DTNB). Thethiopeptolide substrate concentration can be varied, for example from 10to 800 μM, to obtain Km and Kcat values. The change in absorbance at 405nm is monitored on a Thermo Max microplate reader (Molecular Devices,Menlo Park, Calif.) at room temperature (22° C.). The calculation of theamount of hydrolysis of the thiopeptolide substrate is based on E₄₁₂=13600 M⁻¹ cm⁻¹ for the DTNB-derived product3-carboxy-4-nitrothiophenoxide. Assays can be carried out with andwithout matrix metalloproteinase inhibitor compounds, and the amount ofhydrolysis can be compared for a determination of inhibitory activity ofthe test compounds.

[0141] It should be appreciated that the assay buffer that can be usedwith stromelysin-1 catalytic domain (“MMP-3CD”) is 50 mM ofN-morpholinoethane sulfonic acid monohydrate (“MES”) at pH 6.0 ratherthan the HEPES buffer at pH 7.0 described above.

[0142] Compounds of Formula I, or a pharmaceutically acceptable saltthereof, are expected to inhibit MMP-13, including MMP-13CD, with IC₅₀'stypically in the range of from about 0.001 micromolar to about 10micromolar, while the compounds are expected to inhibit full lengthMMP-1, full length MMP-2, MMP-3CD, full length MMP-7, full length MMP-9,MMP-12 catalytic domain, and MMP-14 catalytic domain with IC₅₀'s in therange of from about 20 micromolar to greater than 100 micromolar.

[0143] The invention compounds of Formula I promise to be potentinhibitors of MMP enzymes and will be especially useful due to theirexpected selective inhibition of MMP-13. Because of their expectedpotent and selective inhibitory activity, the invention compounds willbe especially useful to treat diseases mediated by the MMP enzymes, andparticularly those mediated by MMP-13.

[0144] Administration of an invention compound of Formula I, or apharmaceutically acceptable salt thereof, to a mammal to treat thediseases mediated by MMP enzymes is preferably, although notnecessarily, accomplished by administering the compound, or the saltthereof, in a pharmaceutical dosage form.

[0145] The compounds of the present invention can be prepared andadministered in a wide variety of oral and parenteral dosage forms.Thus, the compounds of the present invention can be administered byinjection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I. The activecompound generally is present in a concentration of about 5% to about95% by weight of the formulation.

[0146] For preparing pharmaceutical compositions from the compounds ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

[0147] In powders, the carrier is a finely divided solid which is in amixture with the finely divided active component.

[0148] In tablets, the active component is mixed with the carrier havingthe necessary binding properties in suitable proportions and compactedin the shape and size desired.

[0149] The powders and tablets preferably contain from 5% or 10% toabout 70% of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

[0150] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

[0151] Liquid form preparations include solutions, suspensions, andemulsions, for example, water or water propylene glycol solutions. Forparenteral injection, liquid preparations can be formulated in solutionin aqueous polyethylene glycol solution.

[0152] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, stabilizing, and thickening agents as desired.

[0153] Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, and other well-known suspending agents.

[0154] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0155] The pharmaceutical preparation is preferably in unit dosage form.In such form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

[0156] The quantity of active component in a unit dose preparation maybe varied or adjusted from 1 to 1000 mg, preferably 10 to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

[0157] In therapeutic use as agents to inhibit a matrixmetalloproteinase enzyme for the treatment of atherosclerotic plaquerupture, aortic aneurism, heart failure, restenosis, periodontaldisease, corneal ulceration, cancer metastasis, tumor angiogenesis,arthritis, or other autoimmune or inflammatory disorders dependent uponbreakdown of connective tissue, the compounds utilized in thepharmaceutical method of this invention are administered at a dose thatis effective to inhibit the hydrolytic activity of one or more matrixmetalloproteinase enzymes. The initial dosage of about 1 mg/kg to about100 mg/kg daily will be effective. A daily dose range of about 25 mg/kgto about 75 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstance is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired. Typicaldosages will be from about 0.1 mg/kg to about 500 mg/kg, and ideallyabout 25 mg/kg to about 250 mg/kg, such that it will be an amount whichis effective to treat the particular disease being prevented orcontrolled.

[0158] The following examples illustrate typical pharmaceuticalcompositions provided by the invention. Tablet Formulation IngredientAmount (mg/tablet) Compound of Example 1 25 Lactose 50 Cornstarch (formix) 10 Cornstarch (paste) 10 Magnesium stearate (1%) 5 Total 100

Composition Example 1

[0159] The compound of Example 1, lactose, and cornstarch (for mix) areblended to uniformity. The cornstarch (for paste) is suspended in 200 mLof water and heated with stirring to form a paste. The paste is used togranulate the mixed powders. The wet granules are passed through a No. 8hand screen and dried at 80° C. The dry granules are lubricated with the1% magnesium stearate and pressed into a tablet. Such tablets can beadministered to a human from one to four times a day for treatment ofatherosclerosis and arthritis. Preparation for Oral Solution IngredientAmount Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), 400 mg[(1,3-benzodioxol-5-ylmethyl)-amide] Sorbitol solution (70% N.F.) 40 mLSodium benzoate 20 mg Saccharin 5 mg Red dye 10 mg Cherry flavor 20 mgDistilled water q.s. 100 mL

Composition Example 2

[0160] The sorbitol solution is added to 40 mL of distilled water, andthe invention compound named pyrimidine-4,6-dicarboxylic acid,(4-carboxy-benzylamide), [(1,3-benzodioxol-5-ylmethyl)-amide] isdissolved therein. The saccharin, sodium benzoate, flavor, and dye areadded and dissolved. The volume is adjusted to 100 mL with distilledwater. Each milliliter of syrup contains 4 mg of invention compound.

Composition Example 3 Parenteral Solution

[0161] In a solution of 700 mL of propylene glycol and 200 mL of waterfor injection is suspended 20 g of the invention compound namedpyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(4-methoxy-benzylamide). After suspension is complete, the pH isadjusted to 6.5 with IN sodium hydroxide, and the volume is made up to1000 mL with water for injection. The formulation is sterilized, filledinto 5.0-mL ampoules each containing 2.0 mL, and sealed under nitrogen.

[0162] As matrix metalloproteinase inhibitors, the compounds of FormulaI are useful as agents for the treatment of multiple sclerosis. They arealso useful as agents for the treatment of atherosclerotic plaquerupture, restenosis, periodontal disease, corneal ulceration, treatmentof burns, decubital ulcers, wound repair, heart failure, cancermetastasis, tumor angiogenesis, arthritis, and other inflammatorydisorders dependent upon tissue invasion by leukocytes

[0163] It should be appreciated that in all invention embodimentsdescribed above or in the claims below, whenever an R group such as, forexample, R¹, R², R³, R⁴, R⁵, or R⁶, or an n group is used more than onceto define an invention compound, each use of the R group is independentof any other use of that same R group or, for that matter, any other Rgroup, unless otherwise specified.

What is claimed is:
 1. A method for inhibiting matrix metalloproteinaseenzymes in a mammal comprising administering an MMP inhibiting amount ofa compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein: R² is hydrogen,halo, hydroxy, C ₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,NO₂, NR⁴R⁵, CN, or CF₃; E is independently O or S, A and B independentlyare OR⁴ or NR⁴R⁵; R⁴ and R⁵ independently are H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, (CH₂)_(n) aryl, (CH₂)_(n) cycloalkyl, (CH₂)_(n)heteroaryl, or R⁴ and R⁵ when taken together with the nitrogen to whichthey are attached complete a 3- to 8-membered ring, containing carbonatoms and optionally containing a heteroatom selected from O, S, or NH,and optionally substituted or unsubstituted, n is an integer from 0 to6.
 2. A method for inhibiting matrix metalloproteinase enzymes in amammal comprising administering an MMP inhibiting amount of a compoundof Formula II

or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen,halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,NO₂, NR⁴R⁵, CN, or CF₃; and each R⁴ and R⁵ independently are H, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (CH₂)_(n) aryl, (CH₂)_(n)cycloalkyl, (CH₂)n heteroaryl, or R⁴ and R⁵ when taken together with thenitrogen to which they are attached complete a 3- to 8-membered ring,containing carbon atoms and optionally containing a heteroatom selectedfrom O, S, or NH, and optionally substituted or unsubstituted.
 3. Amethod for inhibiting matrix metalloproteinase enzymes in a mammalcomprising administering an MMP inhibiting amount of a compound ofFormula III

or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen,halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,NO₂, NR⁴R⁵, CN, or CF₃, R⁴ and R⁵ independently are H, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, (CH₂)_(n) aryl, (CH₂)_(n) cycloalkyl,(CH₂)_(n) heteroaryl, or R⁴ and R⁵ when taken together with the nitrogento which they are attached complete a 3- to 8-membered ring containingcarbon atoms and optionally containing a heteroatom selected from O, S,or NH, and optionally substituted or unsubstituted.
 4. A method forinhibiting matrix metalloproteinase enzymes in a mammal comprisingadministering an MMP inhibiting amount of a compound of Formula IV

or a pharmaceutically acceptable salt thereof, wherein n is 0 to 6; R²is hydrogen, halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, NO₂, NR⁴R⁵, CN, or CF₃; each R⁴ and R⁵ independently areH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (CH₂)_(n) aryl, (CH₂)_(n)cycloalkyl, (CH₂)_(n) heteroaryl, or R⁴ and R⁵ when taken together withthe nitrogen to which they are attached complete a 3- to 8-memberedring, containing carbon atoms and optionally containing a heteroatomselected from O, S, or NH. and optionally substituted or unsubstituted,and R⁶, R⁷, R⁸, and R⁹ independently are hydrogen, halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, nitro, or NH₂
 5. A method for inhibiting matrixmetalloproteinase enzymes in a mammal comprising administering an MMPinhibiting amount of a compound of Formula V

or a pharmaceutically acceptable salt thereof, wherein n is 0 to 6; R²is hydrogen, halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, NO₂, NR⁴R⁵, CN, or CF₃; R⁴ and R⁵ independently are H,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (CH₂)_(n) aryl, (CH₂)_(n)cycloalkyl, (CH₂)_(n) heteroaryl, or R⁴ and R⁵ when taken together withthe nitrogen to which they are attached complete a 3- to 8-memberedring, containing carbon atoms and optionally containing a heteroatomselected from O, S, or NH, and optionally substituted or unsubstituted;Each Ar independently is aryl or Het, Aryl is phenyl or substitutedphenyl; Het is an unsubstituted or substituted heteroaryl group
 6. Acompound having Formula I

or a pharmaceutically acceptable salt thereof, wherein: R² is hydrogen,halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,NO₂, NR⁴R⁵. CN, or CF₃, E is independently O or S, A and B independentlyare OR⁴ or NR⁴R⁵; R⁴ and R⁵ independently are H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, (CH₂)_(n) aryl, (CH₂)_(n) cycloalkyl, (CH₂)_(n)heteroaryl, or R⁴ and R⁵ when taken together with the nitrogen to whichthey are attached complete a 3- to 8-membered ring containing carbonatoms and optionally containing a heteroatom selected from O, S. or NH,and optionally substituted or unsubstituted, n is an integer from 0 to
 67. A compound of Formula II

or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen,halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,NO₂, NR⁴R⁵, CN, or CF₃; and each R⁴ and R⁵ independently are H, C ₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (CH₂)_(n) aryl, (CH₂)_(n)cycloalkyl, (CH₂)_(n) heteroaryl, or R⁴ and R⁵ when taken together witha nitrogen to which they are both attached complete a 3- to 8-memberedring, containing carbon atoms and optionally containing a heteroatomselected from O, S, or NH, and optionally substituted or unsubstituted;n is an integer from 0 to 6
 8. A compound of Formula III

or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen.halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl.NO₂, NR⁴R⁵, CN, or CF₃, R⁴ and R⁵ independently are H, C₁-C₆ alkyl,C₂-C₆ alkenyl C₂-C₆ alkynyl, (CH₂)_(n) aryl, (CH₂)_(n) cycloalkyl,(CH₂)_(n) heteroaryl, or R⁴ and R⁵ when taken together with the nitrogento which they are attached complete a 3- to 8-membered ring containingcarbon atoms and optionally containing a heteroatom selected from O, S,or NH, and optionally substituted or unsubstituted; n is an integer from0 to
 6. 9. A compound of Formula IV

or a pharmaceutically acceptable salt thereof, wherein Each nindependently is an integer of from 0 to 6; R² is hydrogen, halo,hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, NO₂,NR⁴R⁵, CN, or CF₃; and R⁶, R⁷, R⁸, and R⁹ independently are hydrogen,halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, nitro, or NH₂; R⁴ and R⁵ independentlyare H, C₁-C₆ alkyl C₂-C₆ alkenyl, C₉-C₆ alkynyl, (CH₂)_(n) aryl(CH₂)_(n) cycloalkyl, (CH₂)_(n) heteroaryl, or R⁴ and R⁵ when takentogether with the nitrogen to which they are attached complete a 3- to8-membered ring containing carbon atoms and optionally containing aheteroatom selected from O, S, or NH, and optionally substituted orunsubstituted.
 10. A compound of Formula V

or a pharmaceutically acceptable salt thereof, wherein n is 0 to 6; R²is hydrogen, halo, hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, NO₂, NR⁴R⁵, CN, or CF3, R⁴ and R⁵ independently are H,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (CH₂)_(n) aryl, (CH₂)_(n)cycloalkyl, (CH₂)_(n) heteroaryl, or R⁴ and R⁵ when taken together withthe nitrogen to which they are attached complete a 3- to 8-membered ringcontaining carbon atoms and optionally containing a heteroatom selectedfrom O, S, or NH, and optionally substituted or unsubstituted Each Arindependently is aryl or Het; Aryl is phenyl or substituted phenyl; Hetis an unsubstituted or substituted heteroaryl group
 11. A compoundselected from: Pyrimidine-4,6-dicarboxylic acid, (4-chloro-benzylamide),[(1,3-benzodioxol-5-ylmethyl)-amide]; Pyrimidine-4,6-dicarboxylic acid,(4-carboxy-benzylamide), [(1,3-benzodioxol-5-ylmethyl)-amide],Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(4-methoxy-benzylamide) Pyrimidine-4,6-dicarboxylic acid,(4-carboxy-benzylamide), (3-methoxy-benzylamide);Pyrimidine-4,6-dicarboxylic acid, (4-carbomethoxy-benzylamide),(3-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid,(4-carboxy-benzylamide), (3-pyridylmethylamide);Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(3-thiophenemethylamide), Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzothiadiazol-5-ylmethyl) amide,[(1,3-benzodioxol-5-ylmethyl)-amide], Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzooxadiazol-5-ylmethyl) amide,[(1,3-benzodioxol-5-ylmethyl)-amide], Pyrimidine-4,6-dicarboxylic acid,(2,1 ,3-benzothiadiazol-5-yl methyl) amide, (4-methoxy-benzylamide);Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl)amide, (3-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acidbis-(1,3-benzodioxol-5-ylmethyl) ester, Pyrimidine-4,6-dicarboxylicacid, bis-(4-chloro-benzylamide); Pyrimidine-4,6-dicarboxylic acid,bis-[(1,3-benzodioxol-5-ylmethyl)-amide], Pyrimidine-4,6-dicarboxylicacid bis-(4-methoxy-benzylamide), Pyrimidine-4,6-dicarboxylic acid,bis-(3-methoxy-benzylamide), Pyrimidine-4,6-dicarboxylic acid,bis-(4-carboxy-benzylamide), and Pyrimidine-4,6-dicarboxylic acid.bis-(4-carbomethoxy-benzylamide)
 12. A pharmaceutical composition,comprising an MMP-13 inhibiting amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier, diluent, or excipient.
 13. Thepharmaceutical composition according to claim 12, comprising an MMP-13inhibiting amount of a compound of Formula 11, or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablecarrier, diluent, or excipient
 14. The pharmaceutical compositionaccording to claim 12, comprising an MMP-13 inhibiting amount of acompound of Formula III. or a pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable carrier, diluent, orexcipient.
 15. The pharmaceutical composition according to claim 12,comprising an MMP-13 inhibiting amount of a compound of Formula IV, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier, diluent, or excipient
 16. Thepharmaceutical composition according to claim 12, comprising an MMP-13inhibiting amount of a compound of Formula V, or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablecarrier, diluent, or excipient
 17. The pharmaceutical compositionaccording to claim 12, comprising a compound selected from:Pyrimidine-4,6-dicarboxylic acid, (4-chloro-benzylamide).[(1,3-benzodioxol-5-ylmethyl)-amide]; Pyrimidine-4,6-dicarboxylic acid,(4-carboxy-benzylamide), [(1,3 -benzodioxol-5-ylmethyl)-amide],Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(4-methoxy-benzylamide), Pyrimidine-4,6-dicarboxylic acid,(4-carboxy-benzylamide), (3-methoxy-benzylamide),Pyrimidine-4,6-dicarboxylic acid, (4-carbomethoxy-benzylamide),(3-methoxy-benzylamide), Pyrimidine-4,6-dicarboxylic acid,(4-carboxy-benzylamide), (3-pyridylmethylamide);Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide),(3-thiophenemethylamide); Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzothiadiazol-5-ylmethyl) amide,[(1,3-benzodioxol-5-ylmethyl)-amide]; Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzooxadiazol-5-ylmethyl) amide,[(1,3-benzodioxol-5-ylmethyl)-amide], Pyrimidine-4,6-dicarboxylic acid,(2,1,3-benzothiadiazol-5-ylmethyl) amide, (4-methoxy-benzylamide);Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl)amide, (3-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl) ester, Pyrimidine-4,6-dicarboxylic acid,bis-(4-chloro-benzylamide), Pyrimidine-4,6-dicarboxylic acid,bis-[(1,3-benzodioxol-5-ylmethyl)-amide]; Pyrimidine-4,6-dicarboxylicacid, bis-(4-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid,bis-(3-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid,bis-(4-carboxy-benzylamide). and Pyrimidine-4,6-dicarboxylic acid.bis-(4-carbomethoxy-benzylamide), or a pharmaceutically acceptable saltthereof, together with a pharmaceutically acceptable carrier, diluent,or excipient
 18. A method for inhibiting an MMP-13 enzyme in an animal,comprising administering to the animal an MMP-13 inhibiting amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof.19. A method for treating a cancer, comprising administering to apatient having cancer and in need of treatment an anticancer effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof.
 20. A method for treating breast carcinoma, comprisingadministering to a patient having cancer and in need of treatment ananticancer effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof
 21. A method for treating heartfailure, comprising administering to a patient in need of treatment aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.
 22. A method for treating inflammation,comprising administering to a patient in need of treatment an effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof.
 23. A method for treating osteoarthritis, comprisingadministering to a patient in need of treatment an effective amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof.24. A method for treating rheumatoid arthritis, comprising administeringto a patient in need of treatment an effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof.
 25. A methodof treating a disease or disorder selected from cancer, heart failure,inflammation, rheumatoid arthritis, and osteoarthritis, comprisingadministering to a patient in need of treatment an effective amount of acompound of Formula II, III, IV, or V. or a pharmaceutically acceptablesalt thereof.